The beta 2 adrenergic receptor has been one of the most extensively studied members of the large family of G protein coupled receptors. Structural domains involved in ligand binding, G protein coupling, regulatory phosphorylation, and agonist mediated receptor internalization have been characterized by chimeric receptor and metagenesis studies. Much of what has been learned about the structural domains of the beta 2 receptor has been shown to be generalized to other members of the family of G protein coupled receptors. While much progress has been made towards understanding the pharmacology and cellular physiology of G protein coupled receptors, the three dimensional structure of the receptor has not been well characterized and the molecular mechanism by which these receptors transmit signals across a lipid bilayer is not known. The overall goal of this research proposal is to further characterize the three dimensional structure of the beta 2 adrenergic receptor, and to identify the structural changes that occur during agonist activation. The Specific Aims include: 1. Develop modified forms of beta 2 adrenergic receptors that will facilitate studies of receptor structure. 2. Determine if receptor oligomerization occurs and is required for signal transduction. 3. Examine the non-covalent interactions between hydrophobic segments 1-5 (domain A) and hydrophobic segments 6 and 7 (domain B), and the role of the structural integrity of the third intracellular loop joining these two domains in receptor function and stability. 4. Characterize the intramolecular relationships of different structural domains in the beta 2 adrenergic receptor, and identify agonist and antagonist specific changes in these structural relationships.